Because macrophages play a major role in
atherosclerotic plaque destabilization, selective removal of macrophages represents a promising approach to stabilize plaques. We showed recently that the
protein synthesis inhibitor cycloheximide, in contrast to
puromycin, selectively depleted macrophages in rabbit
atherosclerotic plaques without affecting smooth muscle cells (SMCs). The mechanism of action of these two translation inhibitors is dissimilar and could account for the differential effects on SMC viability. It is not known whether selective depletion of macrophages is confined to
cycloheximide or whether it can also be achieved with translation inhibitors that have a similar mechanism of action. Therefore, in the present study, we investigated the effect of
anisomycin, a translation inhibitor with a mechanism of action similar to
cycloheximide, on macrophage and SMC viability. In vitro,
anisomycin induced apoptosis of macrophages in a concentration-dependent manner, whereas SMCs were only affected at higher concentrations. In vivo,
anisomycin selectively decreased the macrophage content of rabbit
atherosclerotic plaques through apoptosis. The
p38 mitogen-activated protein kinase (MAPK) inhibitor
SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-
imidazole] prevented
anisomycin-induced macrophage death, without affecting SMC viability.
SB202190 decreased
anisomycin-induced
p38 MAPK phosphorylation, did not alter c-Jun NH(2)-terminal
kinase (JNK) phosphorylation, and increased
extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. The latter effect was abolished by the
mitogen-activated protein kinase kinase 1/2 inhibitor
U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)
butadiene ethanolate], although the prevention of
anisomycin-induced macrophage death by
SB202190 remained unchanged. The JNK phosphorylation inhibitor
SP600125 did not affect
anisomycin-induced macrophage or SMC death. In conclusion,
anisomycin selectively decreased the macrophage content in rabbit
atherosclerotic plaques, indicating that this effect is not confined to
cycloheximide.
p38 MAPK, but not ERK1/2 or JNK, plays a major role in
anisomycin-induced macrophage death.